The results summarized below were obtained in collaborative studies. M4 muscarinic receptors as potential targets for the treatment of Parkinsons disease The striatum is a key component of the basal ganglia circuitry controlling action selection and habit learning. A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. However, it remains unclear how this interaction modulates corticostriatal synaptic plasticity underlying learned actions, particularly as far as direct-pathway spiny projection neurons are involved (dSPNs). In collaboration with Dr. James Surmeier's lab, we demonstrated that cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses in dSPNs by suppressing the activity of RGS4, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-DOPA-induced dyskinesia in Parkinsons disease, administration of a positive allosteric modulator (PAM) of the M4R blocked aberrant LTP in dSPNs, triggered LTP reversal, and attenuated the symptoms of dyskinesia. Interestingly, an M4R PAM also was effective in a primate model of L-DOPA-induced dyskinesia. These findings demonstrate the existence of an important signaling pathway controlling striatal synaptic plasticity that could be targeted pharmacologically for alleviating motor deficits in patients suffering from Parkinsons disease. (Shen W, Plotkin JL, Francardo V, Ko WK, Xie Z, Li Q, Fieblinger T, Wess J, Neubig RR, Lindsley CW, Conn PJ, Greengard P, Bezard E, Cenci MA, Surmeier DJ. M4 muscarinic receptor signaling ameliorates striatal plasticity deficits in models of L-DOPA-induced dyskinesia. Neuron 88, 762-73, 2015.) M4 muscarinic receptors as potential targets for the treatment of schizophrenia Recent studies suggest that muscarinic receptors represent a promising new therapeutic target for the treatment of schizophrenia. However, the molecular mechanisms through which certain muscarinic ligands exert their antipsychotic actions are not well understood. In collaboration with Dr. Jeff Conn's lab, we demonstrated that activation of M4 receptors on medium spiny neurons results in a sustained depression of striatal dopamine release that is observed for an extended period even after removal of the muscarinic agonist. We also found that the M4 receptor-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy in reversing disrupted pre-pulse inhibition require intact signaling through CB2 cannabinoid receptors. Thus, these findings highlight a novel mechanism through which striatal cholinergic and cannabinoid signaling causes a sustained decrease in dopaminergic transmission associated with behavioral effects predictive of antipsychotic efficacy. (Foster DJ, Wilson JM, Muhammad MS, Wess J, Patel S, Marnett LJ, Niswender CM, Jones CK, Xiang Z, Lindsley CW, Rook JR, Conn PJ. Antipsychotic-like effects of M4 receptor positive allosteric modulators are mediated by CB2 cannabinoid receptor-dependent inhibition of dopamine release. Neuron, in press) Review in press: Brown J, Brandl K, Wess J. Chapter 9. Muscarinic Receptor Agonists and Antagonists. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, eds. Brunton LL, Chabner BA, Knollmann BC, McGraw-Hill, New York, NY, 2016, in press.